Most patient with sepsis and septic shock develop significant derangements of myocardial function. The presence of a circulating myocardial depressant substance (MDS) has been suggested to be the major cause of myocardial depression in sepsis and septic shock. MDS is still not fully characterized by chemical means, and there is no consensus regarding its identity. Nevertheless, high levels of MDS activity can be found in sera from patients with sepsis and septic shock. Furthermore, MDS has been shown to have a number of specific characteristics. These characteristics have also been described with tumor necrosis factor-alpha (TNF), a cytokine that is well recognized to be a primary mediator in the pathogenesis of infection, tissue injury, inflammation and shock. In this review it is suggested that TNF is an MDS, and that the cardiovascular injury and myocardial depression during sepsis and septic shock involve a final common pathway, where TNF may have an important role in this common pathway.